This application entitled Circadian Dysfunction, Encephalopathy, and Cognitive Outcomes after Critical Illness is being submitted by Dr. Matthew Maas for a Mentored Patient-Oriented Research Career Development Award. The circadian rhythm is a brain-controlled pattern of neurologic and hormonal signals that influence alertness, sleep, metabolism, body temperature, immune system activity, and other fundamental body functions that maintain homeostasis and health. Research over the last several years has shown that basic cellular health in the brain is negatively affected when the circadian rhythm is abnormal. Moreover, there is evidence that disruption of the circadian rhythm is common and severe in critically ill patients. Critically ill patients suffer inordinate risk of encephalopathy a condition of generalized brain dysfunction that can range in severity from mild to severe (coma), and those patients who develop encephalopathy are at increased risk of death or poor cognitive function for months or years after their illness. Neither the impact of circadian disruption during clinical illness nor the underlying causes of encephalopathy are well understood. This proposal will investigate whether disruption of the circadian rhythm is linked to the risk of encephalopathy and poor cognitive outcomes in critically ill patients. To accomplish this task, we will utilize methods that have been used to study circadian function in healthy patients, including non-invasive electrical recording of brain activity and blood samples to detect the level of the brain hormone melatonin, and combine them with critical care research methods for assessing encephalopathy and cognitive outcomes. Establishing whether a true association exists between these phenomena will allow us to develop strategies to prevent or treat circadian dysfunction with the goal of improving outcomes for severely ill patients. Dr. Maas is a neurologist and critical care specialist now appointed as an Assistant Professor of Neurology and Anesthesiology at Northwestern University. His overarching career goal is to improve the outcome of neurologic injuries in critically ill patients. His clinical training and prior experienes with patient-oriented research make him an ideal candidate to carry out this cross-disciplinary research. He will be supported by a team of experienced investigators with complementary expertise. Dr. Phyllis Zee, his primary mentor, is an expert in the field of circadian biology. Drs Andrew Naidech and Shyam Prabhakaran are accomplished researchers who study complications that affect outcomes for severely ill patients with neurologic injury. This award is mentored program designed to combine the experience of conducting this study with a career development plan for Dr. Maas. The training program will help him build his knowledge base around the science of circadian biology, methods used by neuroscientists to monitor brain function, study design, biostatistics, and other clinical research skills, with the goal the he wil become a productive independent clinical researcher.